Inhibition of integrin α Vβ6 changes fibril thickness of stromal collagen in experimental carcinomas.

Olof Olsson P, Gustafsson R, Salnikov AV, Göthe M, Zeller KS, Friman T, Baldetorp B, Koopman LA, Weinreb PH, Violette SM, Kalamajski S, Heldin NE, Rubin K

Cell Commun. Signal 16 (1) 36 [2018-07-02; online 2018-07-02]

Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF-β1 and -β3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma. The potential role of α Vβ6 integrin-mediated activation of latent TGF-β was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal αVβ6 integrin-specific monoclonal antibody 3G9 was used to inhibit the αVβ6 integrin activity. Both KAT-4 and Capan-2 cells expressed the α Vβ6 integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-β in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-β1 and -β3 reduced collagen fibril thickness in both tumor models. Our data demonstrate that the α Vβ6-directed activation of latent TGF-β plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to αVβ6 inhibition depends on the simultaneous presence of alternative paths for latent TGF-β activation and the extent of desmoplasia.

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PubMed 29966518

DOI 10.1186/s12964-018-0249-7

Crossref 10.1186/s12964-018-0249-7

10.1186/s12964-018-0249-7

pmc PMC6027735